Extracellular Matrix Density Regulates Extracellular Proteolysis via Modulation of Cellular Contractility

Das, Alakesh; Kapoor, Aastha; Mehta, Gunjan; Ghosh, Santanu; Sen, Shamik

doi:10.4172/2157-2518.s13-003

Cited by 14 publications

(18 citation statements)

References 47 publications

(54 reference statements)

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“…This implies that it is the tugging force that is responsible for the maturation of invadopodia and not the stiffness of the matrix. Furthermore, other studies performed in 2D cultures have shown that increasing collagen matrix stiffness results in an increase in the number of invadopodia (Alexander et al, 2008;Artym et al, 2015;Das et al, 2013). While our study has found that the number of invadopodia is unaffected by tugging forces, the length is, however, clearly affected.…”

Section: Discussioncontrasting

confidence: 55%

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Gasparski

Ozarkar

Beningo

2017

Journal of Cell Science

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Cancer cell invasion is influenced by various biomechanical forces found within the microenvironment. We have previously found that invasion is enhanced in fibrosarcoma cells when transient mechanical stimulation is applied within an in vitro mechano-invasion assay. This enhancement of invasion is dependent on cofilin (CFL1), a known regulator of invadopodia maturation. Invadopodia are actin-rich structures present in invasive cancer cells that are enzymatically active and degrade the surrounding extracellular matrix to facilitate invasion. In this study, we examine changes in gene expression in response to tugging on matrix fibers. Interestingly, we find that integrin β3 expression is downregulated and leads to an increase in cofilin activity, as evidenced by a reduction in its Ser3 phosphorylation levels. As a result, invadopodia lengthen and have increased enzymatic activity, indicating that transient mechanical stimulation promotes the maturation of invadopodia leading to increased levels of cell invasion. Our results are unique in defining an invasive mechanism specific to the invasive process of cancer cells that is triggered by tugging forces in the microenvironment, as opposed to rigidity, compression or stretch forces.

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Section: Discussioncontrasting

confidence: 55%

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Gasparski

Ozarkar

Beningo

2017

Journal of Cell Science

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“…3E,F ). Together, these results suggest that increase in MMP secretion rate leads to increased invasion and ECM degradation 23 .…”

Section: Resultsmentioning

confidence: 67%

“…Whenever a cell comes in contact with ECM fibre(s) it secretes MMPs at the rate of λ per second at the site of ECM fibre(s), where λ represents the intrinsic MMP production rate. This ECM-dependent MMP secretion rule was chosen in line with our observations that increase in ECM density enhances MMP secretion 23 . Similar ECM density-dependent MMP secretion profile was observed when MCF-7 cells were cultured on collagen with varying densities ( Supp.…”

Section: Methodsmentioning

confidence: 99%

“…Increase in ECM density and crosslinking progressively stiffen the ECM, which in turn influences cell motility through increased integrin signalling 21 . Interestingly, integrin signalling also influences ECM remodeling via activation of MMPs, which generate migration tracks by proteolytic cleavage of the ECM through membrane-localized as well as soluble MMPs 11 22 23 . Given the wide heterogeneity in ECM organization, invading tumour cells are confronted with different extracellular structures, which in turn are likely to influence the mode of motility in multiple ways.…”

mentioning

confidence: 99%

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Proteolytic and non-proteolytic regulation of collective cell invasion: tuning by ECM density and organization

Kumar

Kapoor

Desai

et al. 2016

Sci Rep

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Cancer cells manoeuvre through extracellular matrices (ECMs) using different invasion modes, including single cell and collective cell invasion. These modes rely on MMP-driven ECM proteolysis to make space for cells to move. How cancer-associated alterations in ECM influence the mode of invasion remains unclear. Further, the sensitivity of the two invasion modes to MMP dynamics remains unexplored. In this paper, we address these open questions using a multiscale hybrid computational model combining ECM density-dependent MMP secretion, MMP diffusion, ECM degradation by MMP and active cell motility. Our results demonstrate that in randomly aligned matrices, collective cell invasion is more efficient than single cell invasion. Although increase in MMP secretion rate enhances invasiveness independent of cell–cell adhesion, sustenance of collective invasion in dense matrices requires high MMP secretion rates. However, matrix alignment can sustain both single cell and collective cell invasion even without ECM proteolysis. Similar to our in-silico observations, increase in ECM density and MMP inhibition reduced migration of MCF-7 cells embedded in sandwich gels. Together, our results indicate that apart from cell intrinsic factors (i.e., high cell–cell adhesion and MMP secretion rates), ECM density and organization represent two important extrinsic parameters that govern collective cell invasion and invasion plasticity.

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“…The collective invasive cell behaviors and patterns are greatly influenced by the heterogeneity of ECM micro-structures. At the molecular level, the ECM protein concentration and ECM components determine the ECM sub-micron structure and mechanical properties [ 9 – 14 ]. At the tissue scale, the structural heterogeneity and anisotropy of native tissues are primarily caused by the complex localized ECM microenvironments and their size, density and orientation.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Invasion of Metastatic Cancer Cells via Extracellular Matrix Interface

et al. 2015

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Cancer cell invasion is a major component of metastasis and is responsible for extensive cell diffusion into and major destruction of tissues. Cells exhibit complex invasion modes, including a variety of collective behaviors. This phenomenon results in the structural heterogeneity of the extracellular matrix (ECM) in tissues. Here, we systematically investigated the environmental heterogeneity facilitating tumor cell invasion via a combination of in vitro cell migration experiments and computer simulations. Specifically, we constructed an ECM microenvironment in a microfabricated biochip and successfully created a three-dimensional (3D) funnel-like matrigel interface inside. Scanning electron microscopy demonstrated that the interface was at the interior defects of the nano-scale molecular anisotropic orientation and the localized structural density variations in the matrigel. Our results, particularly the correlation of the collective migration pattern with the geometric features of the funnel-like interface, indicate that this heterogeneous in vitro ECM structure strongly guides and promotes aggressive cell invasion in the rigid matrigel space. A cellular automaton model was proposed based on our experimental observations, and the associated quantitative analysis indicated that cell invasion was initiated and controlled by several mechanisms, including microenvironment heterogeneity, long-range cell-cell homotype and gradient-driven directional cellular migration. Our work shows the feasibility of constructing a complex and heterogeneous in vitro 3D ECM microenvironment that mimics the in vivo environment. Moreover, our results indicate that ECM heterogeneity is essential in controlling collective cell invasive behaviors and therefore determining metastasis efficiency.

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Extracellular Matrix Density Regulates Extracellular Proteolysis via Modulation of Cellular Contractility

Cited by 14 publications

References 47 publications

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Transient mechanical strain promotes the maturation of invadopodia and enhances cancer cell invasion in vitro

Proteolytic and non-proteolytic regulation of collective cell invasion: tuning by ECM density and organization

Enhanced Invasion of Metastatic Cancer Cells via Extracellular Matrix Interface

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